HSP27 is a member of the small heat shock protein family, a group of ubiquitous stress proteins that are expressed in virtually all organisms. The expression of HSP27 is markedly induced in the brain after cerebral ischemia, and experimental evidence suggests that HSP27 is a promising endogenous neuroprotectant against injury-induced neuronal cell death. The studies outlined in this proposal attempt to investigate the neuroprotective effect of HSP27 and the underlying molecular mechanism in models of cerebral ischemia. The overall hypothesis to be tested is that enhanced expression and phosphorylation- dependent activation of HSP27 protects against ischemic brain injury via novel anti-apoptotic mechanisms. We have recently created transgenic mice overexpressing either the wild-type HSP27 or a non- phosphorylatable HSP27 mutant. Using both transgenic and gene-transfection approaches, we have obtained exciting preliminary results suggesting that overexpression of HSP27 protects against ischemic cell death in both in vivo and in vitro settings, that the neuroprotective effect of HSP27 is dependent on phosphorylation-mediated activation of the protein, and that HSP27 may achieve the neuroprotective effect by directly inhibiting ASK1 and ASK1-dependent apoptosis signaling pathways. The proposed studies outlined in this application will further explore HSP27 as a neuroprotective molecule in cerebral ischemia, and results from this research may have future therapeutic implications for stroke. The following specific objectives are proposed:
Aim 1. Test the hypothesis that transgenic overexpression and phosphorylation-dependent activation of HSP27 protects against focal ischemic brain injury.
Aim 2. Test the hypothesis that the neuroprotective effect of HSP27 against ischemic neuronal injury is mediated via novel anti-apoptotic mechanisms involving the disruption of ASK1-dependent apoptosis signaling pathways.
Aim 3. Test the hypothesis that TAT protein transduction domain-mediated delivery of HSP27 into the brain protects against focal ischemic brain injury. Studies in both in vivo and in vitro models are proposed. The in vivo animal model of focal cerebral ischemia mimics many aspects of pathophysiological changes in the brain after clinical ischemia. The in vitro models will complement the in vivo studies by allowing for precise mechanistic studies to be performed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056118-05
Application #
7871408
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Bosetti, Francesca
Project Start
2006-07-12
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$287,184
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jiang, Xiaoyan; Andjelkovic, Anuska V; Zhu, Ling et al. (2018) Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol 163-164:144-171
Shi, Yejie; Jiang, Xiaoyan; Zhang, Lili et al. (2017) Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury. Proc Natl Acad Sci U S A 114:E1243-E1252
Shi, Yejie; Zhang, Lili; Pu, Hongjian et al. (2016) Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury. Nat Commun 7:10523
Shi, Hong; Wang, Hai-Lian; Pu, Hong-Jian et al. (2015) Ethyl pyruvate protects against blood-brain barrier damage and improves long-term neurological outcomes in a rat model of traumatic brain injury. CNS Neurosci Ther 21:374-84
An, Chengrui; Shi, Yejie; Li, Peiying et al. (2014) Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair. Prog Neurobiol 115:6-24
Hu, Xiaoming; Liou, Anthony K F; Leak, Rehana K et al. (2014) Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles. Prog Neurobiol 119-120:60-84
Wang, Jiayin; Shi, Yejie; Zhang, Lili et al. (2014) Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke. Neurobiol Dis 68:91-103
Stetler, R Anne; Leak, Rehana K; Gan, Yu et al. (2014) Preconditioning provides neuroprotection in models of CNS disease: paradigms and clinical significance. Prog Neurobiol 114:58-83
Anne Stetler, R; Leak, Rehana K; Gao, Yanqin et al. (2013) The dynamics of the mitochondrial organelle as a potential therapeutic target. J Cereb Blood Flow Metab 33:22-32
Leak, Rehana K; Zhang, Lili; Luo, Yumin et al. (2013) Peroxiredoxin 2 battles poly(ADP-ribose) polymerase 1- and p53-dependent prodeath pathways after ischemic injury. Stroke 44:1124-34

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